A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
Authors: Jessica L. Chitty, Michelle Yam, Lara Perryman, Amelia L. Parker, Joanna N. Skhinas, Yordanos F. I. Setargew, Ellie T. Y. Mok, Emmi Tran, Rhiannon D. Grant, Sharissa L. Latham, Brooke A. Pereira, Shona C. Ritchie, Kendelle J. Murphy, Michael Trpceski, Alison D. Findlay, Pauline Melenec, Elysse C. Filipe, Audrey Nadalini, Sipiththa Velayuthar, Gretel Major, Kaitlin Wyllie, Michael Papanicolaou, Shivanjali Ratnaseelan, Phoebe A. Phillips, George Sharbeen, Janet Youkhana, Alice Russo, Antonia Blackwell, Jordan F. Hastings, Morghan C. Lucas, Cecilia R. Chambers, Daniel A. Reed, Janett Stoehr, Claire Vennin, Ruth Pidsley, Anaiis Zaratzian, Andrew M. Da Silva, Michael Tayao, Brett Charlton, David Herrmann, Max Nobis, Susan J. Clark, Andrew V. Biankin, Amber L. Johns, David R. Croucher, Adnan Nagrial, Anthony J. Gill, Sean M. Grimmond, Lorraine A. Chantrill, Angela Chou, Tanya Dwarte, Xanthe L. Metcalf, Gloria Jeong, Lara Kenyon, Nicola Waddell, John V. Pearson, Ann-Marie Patch, Katia Nones, Felicity Newell, Pamela Mukhopadhyay, Venkateswar Addala, Stephen Kazakoff, Oliver Holmes, Conrad Leonard, Scott Wood, Oliver Hofmann, Jaswinder S. Samra, Nick Pavlakis, Jennifer Arena, Hilda A. High, Ray Asghari, Neil D. Merrett, Amitabha Das, Peter H. Cosman, Kasim Ismail, Alina Stoita, David Williams, Allan Spigellman, Duncan McLeo, Judy Kirk, James G. Kench, Peter Grimison, Charbel Sandroussi, Annabel Goodwin, R. Scott Mead, Katherine Tucker, Lesley Andrews, Michael Texler, Cindy Forrest, Mo Ballal, David Fletcher, Maria Beilin, Kynan Feeney, Krishna Epari, Sanjay Mukhedkar, Nikolajs Zeps, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Andrew D. Clouston, Andrew P. Barbour, Thomas J. O’Rourke, Jonathan W. Fawcett, Kellee Slater, Michael Hatzifotis, Peter Hodgkinson, Mehrdad Nikfarjam, James R. Eshleman, Ralph H. Hruban, Christopher L. Wolfgang, Aldo Scarpa, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Nigel B. Jamieson, David K. Chang, Stephan B. Dreyer, Lea Abdulkhalek, Tatjana Schmitz, Victoria Lee, Kym Pham Stewart, Mehreen Arshi, Angela M. Steinmann, Marina Pajic, Paul Timpson, Wolfgang Jarolimek, Thomas R. Cox
Journal: Nature Cancer (2023)

Abstract The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.